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PNAS 98 (20): 11598-11603

Copyright © 2001 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / MEDICAL SCIENCES

A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus

Lindsey D. Mayo David B. Donner*

Department of Microbiology and Immunology, Indiana University School of Medicine, and the Walther Oncology Center, Indianapolis, IN 46202

Received for publication April 11, 2001.

Abstract: The Mdm2 oncoprotein promotes cell survival and cell cycle progression by inhibiting the p53 tumor suppressor protein. To regulate p53, Mdm2 must gain nuclear entry, and the mechanism that induces this is now identified. Mitogen-induced activation of phosphatidylinositol 3-kinase (PI3-kinase) and its downstream target, the Akt/PKB serine-threonine kinase, results in phosphorylation of Mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of Mdm2 from the cytoplasm into the nucleus. Pharmacological blockade of PI3-kinase/Akt signaling or expression of dominant-negative PI3-kinase or Akt inhibits nuclear entry of Mdm2, increases cellular levels of p53, and augments p53 transcriptional activity. Expression of constitutively active Akt promotes nuclear entry of Mdm2, diminishes cellular levels of p53, and decreases p53 transcriptional activity. Mutation of the Akt phosphorylation sites in Mdm2 produces a mutant protein that is unable to enter the nucleus and increases p53 activity. The demonstration that PI3-kinase/Akt signaling affects Mdm2 localization provides insight into how this pathway, which is inappropriately activated in many malignancies, affects the function of p53.

* To whom reprint requests should be addressed at: The Walther Oncology Center, Indiana University School of Medicine, 1044 West Walnut Street, Indianapolis, IN 46202. E-mail: ddonner{at}IUPUI.edu.

Edited by Pedro M. Cuatrecasas, University of California at San Diego, School of Medicine, Rancho Santa Fe, CA, and approved July 3, 2001

This paper was submitted directly (Track II) to the PNAS office.

See commentary on page 10983.

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Statins induce mammalian target of rapamycin (mTOR)-mediated inhibition of Akt signaling and sensitize p53-deficient cells to cytostatic drugs..
E. Roudier, O. Mistafa, and U. Stenius (2006)
Mol. Cancer Ther. 5, 2706-2715
   Abstract »    Full Text »    PDF »
PYK2 mediates anti-apoptotic AKT signaling in response to benzo[a]pyrene diol epoxide in mammary epithelial cells.
A. D. Burdick, I. D. Ivnitski-Steele, F. T. Lauer, and S. W. Burchiel (2006)
Carcinogenesis 27, 2331-2340
   Abstract »    Full Text »    PDF »
Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma.
M. Rudelius, S. Pittaluga, S. Nishizuka, T. H.-T. Pham, F. Fend, E. S. Jaffe, L. Quintanilla-Martinez, and M. Raffeld (2006)
Blood 108, 1668-1676
   Abstract »    Full Text »    PDF »
Ganglioside GM3 modulates tumor suppressor PTEN-mediated cell cycle progression--transcriptional induction of p21WAF1 and p27kip1 by inhibition of PI-3K/AKT pathway.
H.-J. Choi, T.-W. Chung, S.-K. Kang, Y.-C. Lee, J.-H. Ko, J.-G. Kim, and C.-H. Kim (2006)
Glycobiology 16, 573-583
   Abstract »    Full Text »    PDF »
Hdm2 Nuclear Export, Regulated by Insulin-like Growth Factor-I/MAPK/p90Rsk Signaling, Mediates the Transformation of Human Cells.
M. W. Jackson, L. E. Patt, G. A. LaRusch, D. B. Donner, G. R. Stark, and L. D. Mayo (2006)
J. Biol. Chem. 281, 16814-16820
   Abstract »    Full Text »    PDF »
An update on molecular genetics of gastrointestinal stromal tumours..
L Tornillo and L M Terracciano (2006)
J. Clin. Pathol. 59, 557-563
   Abstract »    Full Text »    PDF »
Loss of p53 impedes the antileukemic response to BCR-ABL inhibition.
H.-G. Wendel, E. de Stanchina, E. Cepero, S. Ray, M. Emig, J. S. Fridman, D. R. Veach, W. G. Bornmann, B. Clarkson, W. R. McCombie, et al. (2006)
PNAS 103, 7444-7449
   Abstract »    Full Text »    PDF »
p53 regulates Btk-dependent B cell proliferation but not differentiation.
N. W. Schmidt, L. D. Mayo, D. B. Donner, and M. H. Kaplan (2006)
J. Leukoc. Biol. 79, 852-859
   Abstract »    Full Text »    PDF »
DNA Damage-Induced Protein 14-3-3 {sigma} Inhibits Protein Kinase B/Akt Activation and Suppresses Akt-Activated Cancer..
H. Yang, Y.-Y. Wen, R. Zhao, Y.-L. Lin, K. Fournier, H.-Y. Yang, Y. Qiu, J. Diaz, C. Laronga, and M.-H. Lee (2006)
Cancer Res. 66, 3096-3105
   Abstract »    Full Text »    PDF »
Akt-Mediated Cisplatin Resistance in Ovarian Cancer: Modulation of p53 Action on Caspase-Dependent Mitochondrial Death Pathway..
X. Yang, M. Fraser, U. M. Moll, A. Basak, and B. K. Tsang (2006)
Cancer Res. 66, 3126-3136
   Abstract »    Full Text »    PDF »
Protein Kinase C Negatively Regulates Akt Activity and Modifies UVC-induced Apoptosis in Mouse Keratinocytes.
L. Li, K. Sampat, N. Hu, J. Zakari, and S. H. Yuspa (2006)
J. Biol. Chem. 281, 3237-3243
   Abstract »    Full Text »    PDF »
Differential Regulation of Cardiomyocyte Survival and Hypertrophy by MDM2, an E3 Ubiquitin Ligase.
A. Toth, P. Nickson, L. L. Qin, and P. Erhardt (2006)
J. Biol. Chem. 281, 3679-3689
   Abstract »    Full Text »    PDF »
Detection of functional single-nucleotide polymorphisms that affect apoptosis.
S. L. Harris, G. Gil, H. Robins, W. Hu, K. Hirshfield, E. Bond, G. Bond, and A. J. Levine (2005)
PNAS 102, 16297-16302
   Abstract »    Full Text »    PDF »

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